Project summary Non-resolving chronic inflammation due to defective homeostatic resolution underlies the pathogenesis of atherosclerosis, a significant cardiovascular complication that imposes enormous health and economic tolls. Studies from the PI?s group and others indicate that the lack of effective homeostatic negative regulators may underlie the run-away inflammation and the pathogenesis of chronic atherosclerosis. The PI?s group has identified that IRAK-M (interleukin-1 receptor associated kinase M) is one of the key negative regulators of monocyte inflammation. At the molecular level, the PI observed that IRAK-M may selectively suppress inflammatory activation of monocytes through suppressing key inflammatory transcription factors such as NF?B and IRF5. At the sub-cellular level, the PI discovered that IRAK-M may maintain and restore cellular homeostasis through facilitating the proper completion of autophagy. At the tissue and pathophysiological level, the PI reported that IRAK-M deficient mice are prone to develop aggravated atherosclerosis, due to enhanced recruitment of low-grade inflammatory monocytes to the aortic plaque. The levels of monocyte IRAK-M are significantly reduced in mice under low-grade inflammatory conditions. The long-term goal is to define novel therapeutic targets for maintaining a proper balance of immune environment and treating atherosclerosis associated with chronic low-grade inflammation. Based on these novel observations, the current objective is to define molecular and cellular mechanisms by which IRAK-M modulates the inflammatory polarization of monocytes during the pathogenesis of atherosclerosis. The central hypothesis is that IRAK-M deficiency may polarize a non-resolving pro-inflammatory monocyte state through affecting autophagy completion and inflammatory signaling exacerbation conducive to the pathogenesis of atherosclerosis. To test this hypothesis, the PI plans to perform the following integrated studies. Aim 1 will test the hypothesis that IRAK-M may maintain monocyte homeostasis through negatively regulating TRAF6-p62 mediated inflammatory signaling pathways. Aim 2 will test the hypothesis that IRAK-M may maintain monocyte homeostasis through facilitating autophagy completion. Aim 3 will test the hypothesis that monocyte polarization due to IRAK-M deficiency plays a key role during the exacerbation of atherosclerosis. Completion of this project will define novel molecular and cellular mechanisms responsible for the defective inflammation resolution in exacerbated atherosclerosis, and facilitate the development of therapeutic strategies in treating atherosclerosis associated with low-grade inflammation.